Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma.

PURPOSE: Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid. Metronomic dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize "off-treatment" exposure resulting in an improved therapeutic ratio. EXPERIMENTAL DESIGN: We tested the hypothesis that hyaluronic acid (HA) conjugates of paclitaxel (TXL; HA-TXL) would exert strong antitumor effects with metronomic (MET) dosing and induce antiangiogenic effects superior to those achieved with MTD administration or with free TXL. Female nude mice bearing SKOV3ip1 or HeyA8 ovarian cancer cells were treated intraperitoneally (i.p.) with MET HA-TXL regimens (or MTD administration) to determine therapeutic and biologic effects. RESULTS: All MET HA-TXL-treated mice and the MTD group revealed significantly reduced tumor weights and nodules compared with controls (all P values < 0.05) in the chemotherapy-sensitive models. However, the MTD HA-TXL-treated mice showed significant weight loss compared with control mice, whereas body weights were not affected in the metronomic groups in HeyA8-MDR model, reflecting reduced toxicity. In the taxane-resistant HeyA8-MDR model, significant reduction in tumor weight and nodule counts was noted in the metronomic groups whereas the response of the MTD group did not achieve significance. While both MTD and metronomic regimens reduced proliferation (Ki-67) and increased apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), only metronomic treatment resulted in significant reductions in angiogenesis (CD31, microvessel density). Moreover, metronomic treatment resulted in substantial increases in thrombospondin-1 (Tsp-1), an inhibitor of angiogenesis. CONCLUSIONS: This study showed that MET HA-TXL regimens have substantial antitumor activity in ovarian carcinoma, likely via a predominant antiangiogenic mechanism.

A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis.

Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a number of human cancers and cancer cell lines. Via its Src homology 2 (SH2) domain, Stat3 is recruited to phosphotyrosine residues on intracellular domains of cytokine and growth factor receptors, whereupon it is phosphorylated on Tyr705, dimerizes, translocates to the nucleus and is reported to participate in the expression of genes related to angiogenesis, metastasis, growth and survival. To block this process, we are developing cell-permeable, phosphatase-stable phosphopeptide mimics, targeted to the SH2 domain of Stat3, that inhibit the phosphorylation of Tyr705 of Stat3 in cultured tumor cells (Mandal et al., J. Med. Chem. 54, 3549-5463, 2011). At concentrations that inhibit tyrosine phosphorylation, these materials were not cytotoxic, similar to recent reports on JAK inhibitors. At higher concentrations, cytotoxicity was accompanied by off-target effects. We report that treatment of MDA-MB-468 human breast cancer xenografts in mice with peptidomimetic PM-73G significantly inhibited tumor growth, which was accompanied by reduction in VEGF production and microvessel density. No evidence of apoptosis or changes in the expression of the canonical genes cyclin D1 or survivin were observed. Thus selective inhibition of Stat3 Tyr705 phosphorylation may be a novel anti-angiogenesis strategy for the treatment of cancer.